Carbohydrate-boric acid salts of amino aromatic bases



Patented Nov. 9, 1948 CARBOHYDRATE-BORIC ACID SALTS OF AMINO AROMATIC BASES David Curtis, New York, N. Y.

No Drawing. Application July 13,1945, Serial No. 604,975 1 The present invention relates to a series of new amino-aromatic salts, and,more particularly, to

9 claim (Cl. 260-209) amino-aromatic salts of a boric acid complex with a carbohydrate.

. It is the object of the present invention to provide a series of new amino-aromatic salts which are of increased solubility.

It is another object of the present invention to provide a new series of salts of the character described which have increased stability in solution.

It is a further object of the present invention to devise methods for preparing the salts of the present invention. 1

It is the general object of the present invention to devise methods and means for imparting increased solubility and greater stability in solution upon amino-aromatic bases and their. boric acid salts than normal for such bases andsalts in a particular solvent. I

It is known that certain soluble carbohydrates have the power of activating boric acid in solution' to a greater degree of dissociation than normal, thus producing strongly acid solutions of boric acid. Presumably, these carbohydrates form complexes with the boric acid in solution, of an ester nature, which are strongly acidic.

I have found that these boric acid-carbohydrate complexes are capable of forming salts with amino-aromatic bases much more easily than the ordinary boric acid and with lesser quantities of boric acid. I have also found that such salts have increased degrees of solubility in water and in other solvents in which the basic substances are either insoluble or have a limited degree of solubility.

It is believed that it is the multiplicity of hydroxyl groups present in the carbohydrate molecules and the favorable disposition of such bydroxyl groups to the formation of ring systems with boric acid that leadsto the formation of the complexes.

Maganini, An. 1890, p. 1357; 1891, p. 251, cites mannitol and dulcitol as increasing the conductivity of boric acid in solution.

J. Boeseken et al., in Rec. Trav. Chim., 1911, v. 30. pp. 392-400, statesthat the two OH groups of polyhydroxy compoundsshould be in the alpha position to one another and should be in the same plane, in order to permit the formation of ring combinations with boric acid.

mono and polyhydroxy alcohols with increasing acidity and conductivity.

.Various carbohydrates may activate boric acid to a different degree of acid potency.

Ukraine Klin. Zhur., v. 11, pp. 433-44, 444-5, 1936, shows dulcitol, xylose, mannose and arabinose as increasing the degree of dissociation of boric acid. The same publication, in vol. 8, pp.

307-15, 1935, citesfructose to be as good as mannitol in increasing dissociation of boric acid and maltose, lactose, glucose, erythritol andgalactose as increasing ionization of boric acid,in the order given, having a lesser efiect than fructose or mannitol; two moles of mannitol per one mole of boric acid producing the magnitude of the effect.

I. Ageno et al., Gazz. Chim. Ital, 43, 2, 163-74, state that the electrolytic dissociation of mannitol-boric acid is of the order of monobasic organic acids (i. e. much stronger than that of boric acid) and is proportional to the concentration of mannitol. They conclude that mannit'ol and boric acid unite in the proportion of 1:1.

J. C. Irvine et al., J. Ch. 800., v. 107, pp. 1221- i 29, 1915, states that Boesekens conclusions that the joint increase in theconductivity shown by certain OH compounds in the presence of boric acid is only encountered when two OH groups are attached to adjacent carbon atoms and are arranged on the same side of the carbon atoms,

1 in the same plane, have been extended to the E. B. R. Prideau, Z. Anorg. Chem., 1913, v. 83,

study of partially methylated derivatives. of mannitol, thus confirming the structure It was shown thatthe OH groups 1 and 2 are primarily responsible for the increase in conductivity.

J. Boeseken et al., in Rec. Trav. Chim., v. 30,.

pp. 392-406, has shown that pentaerythritol (CHzOI-I)3C(CH2OH) is capable of forming two ring systems with boric acid and its influence on the conductivity of boric acid is enormous; which would indicate that the two end OH groups are in a favorable position to form the ring systems with the boric acid.

Jones, in Amer. J. Sci, 1899, v. 7, p. 147, shows it is a well known fact that the addition of mannitol and other polyhydroxy alcohols to a water solution of boric acid results in the formation of a strong acid in the liquid. If suflicient mannitol is present boric acid will act as a monobasic acid as regards the titration with NaOH solution.

Vignon, Ann. Chim. Phys, 1874, v. 2,. p. 433,

J. J. Fox et al., J. Chem. Soc. of London, v. 33'," p. 1075, 1911, show the isolation of mannitoboric.

acid, 1:1 mannitol and boric acid, and also show that an excess of either boric acid or mannitol 4 tetra-saccharides, and have the general formula of (CsHiuOsMHzO, where 12 may be 2, 3 or 4.

The monosaccharides, aldoses, are known as monoses and those containing the ketone group are known as ketoses. According to the number of carbon atoms the monosaccharide carbohydratecontains' it is classified as tetrose, pentose, hexose, heptose, octose and monose.

While this invention concerns itself, principally,

with the carbohydrate-boric acid complexes formed from the hexoses, the alcohols derived from these hexoses, the hexitols, and the inner anhydrides of these hexitols, the hexitans and the hexides, the invention comprehends likewise, the use of all carbohydrates capable of activating boricacid to a greater degree of acidity,

favors the formation of this compound, CeI-IrsOsB.

Jo Yun Tung et al., in the J. Chinese. Chem. 800., v. 9, pp. 125-33, 1942, states that, generally, the boric acid complex with a carbohydrate may be represented as EAn, where B is the borate ion, n is 2, and A may be mannitol, xylose, fructose, arabinose; and the structural formula of the complex is represented by H. Schaefer, in Z Anorg. Allgem. Chem., 2&7, 96-112, 1941, states that activating boric acid by different carbohydrates, such as mannitol, fructose, erythritol, indicated the predominance of the HBDz complexes, D standing for the carbohydrate. By the addition of suflicient mannitol or fruc: tose it may be possible to titrate boric acid at a DH of 6.

L. Ambert, Compt. Rend., 108, 1016-1017, states that it is confirmed that mannitol, erythritol, dextrose, levulose or galactose, when mixed with a small quantity of boric acid or a diborate, the solution is strongly acid. He also finds that arabinose, arabitol, dulcitol and mannitol form similar acid solutions. He concludes that polyhydric alcohols which contain a primary alcoholic function combine with boric acid to form energetic conjugated acids which decompose carbonates.

' The carbohydrates which will activate boric acid to form the acid complexes which will combine with the amino-aromatic bases to form the salts of the present invention include polyhydroxy aldehydes or aldoses and polyhydroxy ketones or ketoses, and the alcohols derived from them by reduction, and the inner ethers of such alcohols derived by splitting ofi oneor two molei cules of water from these alcohols.

The term carbohydrates as used herein also includes those substances which yield the aldoses and ketoses above named when hydrolyzed by treatment with mineral acids or through enzymatic action.

The general formula for the aldoses may be statedv to be CH2OH(CHOH) nCHO. For the purposes of this invention, 11 represents the number 2jor a greater number.

The general formula for the ketoses is CHzOH (CI-10H) nCOCH2OH Where n represents 1 or a greater number,

The carbohydrate alcohols contemplated in the present invention have the formula CHzOH (CHOH) nCH2OH where n represents the number 2, or a greater number.

The polysaccharides include the di-, triand the..complex of a greater degree of solubility... in

water. or in other solvents than itself.. a The tetroses include erythrose; its ketonic form erythroketose; and its alcohol, erythrol.

The pentoses include arabinose, ribose, xylose and the alkyl pentoses, such as rhamnosev (methy1 pentose, (C5H9(CH)305) the respectiveketones of the foregoing, and their alcohols, such as adbnitol, derived from ribose.

' The hexoses include glucose (dextrose), gulose, manose, galactose; their ketone forms, suchas fructose (laevulose), sorbose, formose, b-acrose, rhamonohexose (CsH11(CH)3Oe), and theiralcohols, which include sorbitol, and mannitol, derived from dextrose; dulcitol, derived from galactose: and' mannitol is also. obtained. on reducing mannose and laevulose.

The heptoses include the mannoheptose, alpha and beto glucoheptose, galah'eptose; andv the keto forms such as fructo-heptose; also rhamnoheptose (methyl heptose) C7H13(CH)'306. The heptose alcohols include persitol which is the same as d'-mannoheptitol. l

"Theoctoses include mannooctose, alpha and beto glucoctose and its alcohol octitol.

' The nonoses include mannononose and glucononose.

The disaccharides include maltose, lactose, melibiose. Among the trisaccharides are included rafiinose, gentianose, melezitose.

Among the polysaccharides suitable for the purposes of thepresent invention I have also found that certain soluble derivatives of cellulose compounds, such as methyl cellulO-seand bydroxyethyl cellulose, which form highly viscous fluids with water, are also capable of causing an increased dissociation of boric acid and" impart to their solutions a strongly acid reaction.

The inner anhydrides of the carbohydrate alcohols may be of the monoanhydride or dianhydride types. The dianhydride of a hexitol, for example, has the general formula the basic substance CHQOH vonoon. onion; 0 l

These. anhydrides include mannide and 'isomannide and. sorbide '--CsHsO2(OH) z; mannitan and sorbitan =-CsHsO(OH)4; also the dianhydride of erythritol.

Among the carbohydrate alcohols is alsoincluded pentaerythritol -(CH'2O'H) 3 C (CI-I2OH) which hasconsiderableactivating power on boric acid.

The carbohydratescontemplated in the present invention. alsoincludethe so called-enol com.-

pounds, which are formed whenv dextrose, mannose and fructose are converted into an enol,

in weakly alkaline solutions.

In the formulation of the compounds of this invention between amino organic bases and boric acid activated by a carbohydrate, depending on the case, I may use an excessof the carbohydrate over the amount of boric acid, or I may use an excess of boric acid over the carbohydrate. Thus, in the case of a weaker base, I would use a greater amount of both, the boric acid and the carbohydrate, so that the excess of either would help the formulation of the complex. I may use enough of the basic substance so that it will combine in at least one molar proportion to the boric acid present and there may also be an excess of orthoboric acid in its conversion to the metaboric boric acid, so that a complex may form on the type of a borax compound, the formula for the product being R.HBDm.(B203) n; :r and n being at least 1.

Where one molar equivalent of the organic base is linked toone molar equivalent of boric acid, the formula would be RHBDm, a: being at least one, D standing for the carbohydrate, R for the organic base.

Where a suitable solvent would permit, I may use an excess of the basic substance over the amount of boric acid present than is required to permit of their unimolar combination. Such preparations may be used by themselves, as for external applications; or they may be utilized as stock solutions, the solution being properly diluted with the same or with another solvent to 1 reduce the active substance to its suitable concentration for the particular purpose. Additional carbohydrate and boric acid may be added as required .tomake up a suitable solution for requisite use.

In making up the solutions of an amino organic basic substance linked to boric acid activated by a carbohydrate sugar or alcohol or inner ether of a carbohydrate alcohol, I may cause the reactants to combine in a suitable vehicle, such as water, glycerol, a glycerol ether such as ethyl,

an alcohol, such as ethyl alcohol, iso-propyl alcohol; the glycols, such as propylene glycol, diethylene gycol, diethylene glycol monethyl ether and other suitable glycol derivatives; a solution of sorbide, sorbitan and the like. The formation of the compound may also take place in amixture of water with any of the above solvents, or mixtures of the solvents.

A solution thus prepared may be ready for use or may be evaporated to dryness from a suitable vehicle, or. the formed compound may be precipi tated from such a vehicle by virtue of the fact that it is insoluble or sparingly soluble in the vehicle employed.

The amino organic basic compound may. be

linked to the carbohydrate-boric acid complex in the same solution in which the complex is originallyformed, or the complex may be first prepared separately and then used as the acid substance to which All of the reactants may be triturated in a little water and then mixed with acetone, or may be triturated with acetone only or with another volatile vehicle and then allowed the volatile vehicle to evaporate under a moderateheat, so that the heating of the components in the presence of the volatile Vehicle in which, preferably, the organic base is solublapromotes the formation methyl or other suitable alkyl ethers of glycerine;

the organic base is to be linked.

volatilizing the vehicle.

Somecarbohydrate-boric acid complexes may be formulated by first triturating the carbohydrate with the boric acid, when frequently a reaction sets in at once, indicated by the formation of a gummy, stringy mass, thenfollowed by the application of a moderate heat, such as by placing the container over a low flame hot plate; the heating soon causing the combination to melt, and further. heating. driving off the water ofthe reaction, some of the Water derived from the acid, andsome derived from the reaction between the H's of theOH of the reactive alcoholic groups or the carbohydrate molecule and the O of the metaboric acid. Theinorganic basic substance may be stirred in at this point, before the water of the reaction has been completely expelled, or it may be incorporatedinto the resinous mass generally formed at the end of the reaction, and the new compound formed by fusion, followed by its dissolutionin a suitable vehicle for recrystallization or for direct use. as desired.

It is also possible to cause the formation of the carbohydrate-boric acid complex as described above, and, while the water of formation is being expelled and reactant mass is still in a fluid state, the amino organic basic substance may be dissolved in a volatile, vehicle, and the solution mixedwiththe molten and still liquid complex material. In some cases the whole may be taken down to dryness at a moderate heat, expelling the last traces of the solvent vehicle under reduced pressure, or removing the vehicle all the way under reduced pressure. Inother cases it is possible to cause a precipitation of the formed compound, the amino organic .salt of the carbohydrate-boric acid complex, filtering off the precipitated mass and then drying it, expelling the final traces of the solvent under reduced pressure. It is also possible to neutralize the acid radicle of a salt ofa particular amino organic compound.

by adding a sufficientamount of a suitable alkaline substance, such as sodium hydroxide, sodium s carbonate, potassium carbonate, or sodium bicar-- bonate, in an equivalent amount to fullycombine with the acid present, and then adding to the base, either precipitated or in solution while freed from the original acid radicle, the proper amount of the desired carbohydrate boric acid complex, previously prepared in solution or. solid form, to produce the new sa1t.,

Another method of forming the newly devel-.

oped salts of amino organic compounds with carbohydrate-boric acid complexes is by double de- 1 composition. A suitable amount of the particuother basic radicle.

lar complexacid is first formulated in solution form, the acidity of the complex is then neutralized withan equivalent amount of. alkali or This alkaline or basic salt is added to a solutionof the basic organic substance linked to some acid radicle will either form "an insoluble salt in the vehicle employed withthat acid radicle, or will cause an ionic transformation toindicate the formation ofthe salt of the initial organic base now linked to the carbohydrate-boric acid complex radicle.

Among the amino organic compounds that may be used to form thesalts of the present invention are included generally any such amino compounds capable of reacting with an acidic substance of the nature described, such as aniline, para amino phenol, para methyl amino phenol (metol) ,and the like. i a

sesame Among the amino compounds of the anaestheticgroup the following may belisted: procaine, butyn, diethylamino propyl para amino benzoate,

dipropylaminoethyl para amino benzoate, di-

pounds wherein the NI-Iz grouping on'the benzene ring is in other than the para. position, and

anaesthetics of the type wherein the aromatic nucleus is other than benzoic acid, such asv cinnamic acid and the like. It also includes compounds of this type wherein the esterifying alcohol may be of the. secondary type instead of the customary tertiarytype, such as mono-ethyl aminopropyl para amino benzoate and thelike, mono: butyl amino propylpara amino benzoatetand thelike.

Among the amino organic compounds of the vaso constrictor type of substancesmay belist'e'd the following: epinephrine, epinine', neo synephrine, ephedrine, ephetonine, tyramin'e, cbbefrine and other similar compounds, consisting, in general, of amino aromatic compounds, hydroxylated or non-hydroxylatedon the benzene nucleus and having an amino alcohol chain or analkyl amino chain, methylated or non-methylat- Among alkaloidal amino organic substances which may be used for the purposes of the pres- .ent invention the following may be listed: caffeine, theobromine, veratrine, quinine, atabrin, ephedrine, brucine and others.

Of the so-called surface anaesthetic amino organic compounds, the following. may be listed: benzocaine, butesin, iso-propy1 paraamino benzoate, orthoform (methyl meta-amino para-oxybenzoate) iso-butyl para amino benzoate and the like.

Among the sulfa compounds which are also capable of combining with the carbohydrate-boric acid complexes described, maybe listed, generally, the amino sulfonyl amides such as sulfanylamide, sulfapyridine, sulfathiazole and sulfadiazine.

Numerous other amino organic compounds are suitable to be linked to the carbohydrate-boric acid complexes to form new and useful substances, some having a therapeutic effect and others suitable for industrial use, such as in photography and other uses.

The salts of the present invention are, in some instances of a balsamicnature, or of a resinous type, or may be of a pulverizable powder, or may be of a vitreous character. Generally they melt or soften easily on the application of heat of the boiling water bath or a low flame hot plate.

Following are a number of examples illustrating the foregoing principles. These examples are representative and are not intended to be limitative, and many more of the "same or other compounds and in 'difierent proportions and combinations are possible. I

As an example of how to formulate'a dimannito-boric acid complex by the direct'unionof'the ingredients, the following may be given: 72.8 gms. oi mannitol (0.4 M.) may be triturated with 12.4 gms. of boric acid (0.2 M.) in a mortar, when soon combination begins to take place as is evidenced by the formation of a gummy stringymaterial. When the material is then transferred into a beaker, placed over a low flame hotxplate, it soon becomes pasty and liquefies. As thewat'eris being driven oiT, the material becomes. resinous; When the water in the equivalent of 3 moles is driven 01f, an. amber, resinlike material .is-.ob--

The above mannltoboriore'sin- (two equim'olesl m'annitol" to one equimole'of boric acid) mayrbe dissolved in water and a suitable amountofran organic base may be stirred in and heated untill the formation of a saltis obtained, or abase'm'ay" beincorporated by fusion. Thus, 18.8'gms. of the:- resihous material, the dimannit'oborate may be. melted over a low heat hot plate and: 5.9"gms: ofprocaine base (0.025 M.) may be'stirred On: removing the beaker from the hot plate and stir-- ring the mix, the material assumes an amber; clear, transparent, balsamic resinous appearance. On cooling, the mass becomes vitreous; amber resin. The material dissolves easily in- Water: on warming, giving an acid reaction to litmus Ammonium hydroxide precipitates'th'e procaine base from this solution.

Another method of preparing a mannitobo'ric acid complex is as'follows: 14156 (15) gms. of mannitol (0.08 M.) are mixed with 3:72 gms. of boric acid (0.06 M.) in the presence of 5 cc. of Water, and the mixis boiled for a few minutes, 100 cc. of isopropyl alcohol are then added and stirred, when the entire mass becomes awhite paste. This is filtered and Washed several times with isopropyl alcohol and then dried; A white pulverizable powderis obtained. This acid complex may be dissolved in Water and a suitable or-' ganic compound may be linked to the'acid in suit able amount.

When 5 gms. of the above powder'are dissolved in cc. of water and brought to a boil, 2.36'g-n1s. of procaine base may be stirred in until solution takes place. The solution has a pH of 6:1 brom thymol blue. i When in the above formulation of the mannitoboric acid 5 gms. of benzocaine are dissolvedinthe isopropyl alcohol and mixed with the carbohy drate boric acid complex, and the filtered mass is'dried, a pulverizable powder is obtained. At least one gram of this material-may be dissolved in cc. of water on heating and it produces a surface anaesthetic. The amount of'benzocaine thus dissolved in water is considerably in excess of the normal solubility of benzocaine in the same medium. The solution remains stable long enough to be used at room temperature.

When 3 gms. of this benzocaine-mannitoboratepowder is dissolved in 100 cc. of Watercontaining' 5' gms. procainebase linked to a-suitable acid; the solution remains stable for some time.

To indicate how procaine base may be combined in unimolar equivalents with boric acid, under suitable conditions, and how itmay lie-rendered soluble, in accordance with the principles of'the present invention, the followingmay be given: 4.72 gms. of procaine base (0.02 M.)a're dissolved in ethyl alcohol and 1.24 gms. oi boric acid (0.02M.) are stirredin and the solution is evaporated to'dryness. A hard mass is obtainedfwhich does not dissolve in water quite readily. It softens on the application of moderate heat overa loW flame hot plate. When 7.28 gms. of mannitol (0.04 M.) are added and the beaker warmed on the hot plate below the boiling point ofwater; solution soon takesplace and register a pHof about 7.1 brom thymol blue. The solution is made up to 100 cc. withwater.

10cc. of'the above solution requires; for titra'-- tion in the presence of '15 cc. of-a'cetone, 4=cc.- o1- a: 0.5:N sodium hydroxide solution; equivalent to' .Soon the benzocaine melts and the heating is continued for several minutes. 50 cc. of.85% of 'sorbide may then be added and the solution brought to a boil, the benzocaine going into solution. Instead of benzocaine, 1.67 gms. of orthoform may be used, or 1.79 gms. of propoesin may be used. 7

Example 2.-'l.28 gms. of mannitol, sorbitol or dulcitol (0.04 M.) and 1.86 gms. of boric acid (0.03 M.) and 1.67 gms. of orthof orm maybe formulated and combined in water and the solution may remain stable long enough tobe used.

. Example 3.-Triturate together 7.28 gms. of sorbitol (0.04. M.) .l.24.gms. ofboric acid (0.02 M.).

.A gummy white paste is formed. When 2.36-gms. of procaine base (0.01 M.) are stirred in and warmed on the water bath, a whitebalsamicmaterial is obtained which dissolves easily in water and gives an acid reaction to methylv red. Under these conditions, a ,lowerpI-I solution is obtained, conducive to .a greater stability. of the solution than when a molar equivalent of HsBOs is used to one equivalent of procaine base as it obtains commercially, and hasa pH of about 8.2 to 8.4 cresol red.. A lower boric acid. content is likewise desirable when the product is used for injection purposes. The above method represents a fusion method of obtaining a. salt-of a carbohydrate alcohol-boric acid complex. 1

Example 4.-Triturate 3.64 gms. (0.02M) of dulcitol with 1.24 gms. (0.02 M.) of boric .acidand 236 gms. of procaine base with acetone and evaporate to dryness on the water bath. A light col- ,1

cred balsamic resinous material is obtained which,

when dissolved in water and made up to 100 00.,

register a pH of about 6.1-6.3 brom thymol blue.

Example 5.- 3.64 gms. of mannito1 (0.02. M.)

are rubbed together with acetone and 2.00 gms.;

of boric acid and 3.8 gins. of procaine base. and taken down to dryness on the water bath. .A balsamic mass is formed whichbecomes vitreous when cooled.

Example 6.- '7.28 gms. of .sorbitol (0.04 M.)v and 1.86 gms. of boric acid (0.03 M.) and 1.65gm. 0f benzocaine (0.01 M.) are triturated with acetone presence of some additional mannitol.

' of an alkalinereaction.

10 and 3.64 gms. of mannitol (0.02 M.) are dissolved and 2.36 gms. of procaine base are stirred in, dissolving easily. The solution is made up to 1 00 cc. with water. 5 cc. of this solution requires 10 cc. of 0.1 N sodium hydroxide for titration in the This is equivalentto 1.24% of free or uncombined boric acid, indicating a balanceof 0.62 gm. of boric acid as combined with the procaine base present in unimolar combination. 0

A possible formula for the above compound would be B..l-IBD2.B2O3, R standing for procaine (base, or for another amino organic base simi larlyreacting and similarly combined. When only a unimolar equivalent of the boric acid is .present to the procaine base, the possible formula is .Rl-lBDz.

When 5 cc. of the above 0.03 M. solution of boric acid are titrated in the presenceoi 1500. of acetone, 15 cc. of the 0.1 N NaOH are required, accounting for the full amount of 1.86 gms.. taken originally in the formulation.

Example 9.Disso1ve 36.4 gms. (0.2 M.) ofm-annitol and.6.2 gms. (0.1 M.) of boric acid in about 10 cc. -oi water and boil for several minutes. Separately dissolve 23.6 gms. of procaine base (0.1M) in about 150 cc. of acetone and bring theftwo solutions together. The containing vessel is placed on the water bath andthe acetonedriven off as the procaine base combines with themannitoboric acid. The combined solutions remain clear for a little while until precipitation of the procaine mannitoborate begins. i

The evaporated material is a resinous, vitreous, brittle substance, becoming balsamic on warming. The material dissolves easilyinthe water andis Example 10.-Disso1ve 14.56 gms.. of mannitol .(0.08 M.) and 2.48 gms. of boric acid (0.04 in 5 cc. of Water and separately dissolve 4.72 gms.,of procaineba'se in 10000. of acetone.; Mixbothsolutionsand stir until precipitation takesplace.

The precipitate is filtered off and driedtoa white powder, pulverizable but easily softeningl on warming. The water solution of this procaine mannitoborate is acid in reaction- Some oLthe reactants escape in the filtrate. i

Using more of boric acidaffords a more vitreous material when evaporated toidryness. {The solution is also more acid, as when, for instancaa .5 molar concentration of boric acid is. used (3.10

- gms.) to two molar equivalents of mannitol (3.64

and taken down to dryness over the water bath.

A balsamic substance is obtained which dissolved easily in 85% of sorbide solution in water.

Example 7.3.64 gms. (0.02 M.) of sorbitol are i triturated with 0.62 gm. (0.01 M.) .of boric acid in i acetone and taken down to dryness, forming a clear balsamic substance. This disorbitol monovborate dissolves easily in water and when made up to 100 cc. may be titrated in thepresence of phenolphthalein. to indicate the full presence of the originally takenboric acid. 1

When 2 3.6 gms. of procaine .base (001: M.) is stirred into the above mixture of: sorbitol. and

boric acid and taken down to dryness, a balsamic,

gms.) to one molar equivalent of procaine.,base (2.36 gms.). The solution in water registers a pH of about.5.75.8, methyl red, in 100 cc. of water, as against. 8.2-8.4 cresolred for the five molar equivalent of boric acid to onecof procaine base.

Example 11.-5.943 gms. ofrafiinose (0.01M), CisHa2O1s.5I-I2O-mo1. wt. 594,33, are dissolved in cc. of Water together with 1.86 gms. (0.03M) of boric acid and 2.36 gms. of procaine base stirred in until the procaine goes into solution. The solution is alkalineto bromthymol blueandwthe procaine may be precipitated by the additionof NH40'H." This is an exampleof a polysaccharide, a trisaccharide, activating boric acid in solution,

so that procaine base may react with it in a proportion less than a 4 molar equivalent of boric acid to one of procaine base.

Example '12.Similarly, procaine base maybe combined. with rhamnose, C(SHIZOE-HZO II IOL wt. 1 2. Using 3.04 .grns. (0.02 M) ofrhamnoseto 2.36 gms. of procaine base (0.01M;) to 1L24Jgms.

.=.0f .boric acid 1 (0.02 M.) thesolution has 1 alka- 1 1 line reaction. This is an example of using a methyl pentose to activate boric acid.

Example 13.1.82 gms. of rhamnose (0.01 M. are triturated with acetone and 1.86 gms. of boric acid (0.03 M.) and 1.72 gms. (0.01 M.) of sulfanile amide and taken down to dryness on the steam bath. A reddish amber material is obtained, the powder resembling shellac.

Example 14.In the above described process of trituration with acetone and evaporating to dryness on the water bath, sorbitan may be substituted for the carbohydrate hexitols.

Thus, 7.56 gms. (0.04 M.) of sorbitan and 1.24 gms. (0.02 M.) of boric acid are triturated in acetone with 2.36 gms. of procaine base previously dissolved therein. On taking down to dryness on the steam bath, a balsamic resinous substance results, which is easily soluble in water.

Example 15.-3.28 gms. (0.02 M.) of sorbitan, 2.48 gms. (0.04 M.) of boric acid and 1.65 gms. of benzocaine are triturated in acetone. When placed on the water bath and warmed the material dissolves. When the solution is taken down to dryness, the evaporated mass presents a light gummy mass, hardening on cooling and dissolving easily on warming in 50 cc. of ethyl glycerine.

Similarly, the sulfonamide compounds of sorbitan borate may be prepared by trituration of the ingredients with acetone and taking the material down to dryness on the water bath.

Example 16.--3.28 gms. of sorbitan (0.02 M.) and 1.86 gms. of boric acid (0.03 M.) are triturated in about 50 cc. of acetone with 1.72 gms. of sulfanilamide or with 2.49 gms. of sulfapyridine, or 2.55 gms. of sulfathiazole or 2.50 gms. of sulfadiazine ([0.01 M.] of base in each instance). The sulfanilamide compound forms a balsamic resinous mass on being taken down to dryness. The sulfapyridine forms a white gummy mass; sulfathiazole a hard mass becoming gummy on heating on the water bath; sulfadiazine a white hard mass. The sulfanilamide compound dissolves easily in water on warming. The sulfapyridine and sulfathiazole compounds dissolve in ethyl glycerine on warming on the water bath. The sulfadiazine compound dissolves in 100 cc. of equal volumes of eth'yl glycerine and 85% of sorbide solution in water.

Example 17.An important preparation may be prepared by dissolving 1.64 gms. (0.01 M.) of sorbitan plus 1.86 gms. of boric acid (0.03 M.) and 1.72 gms. of sulfanilarnide in about 10 cc. of alcohol, then mixing the solution with 40 cc. of the commercial collodion used for application to the skin. 1.65 gins. of benzocaine may be used in place of or together with the sulfanilamide in the above preparation.

Example 18.-3.60 gms. of deXtrSeCsH120s (0.02 M.), 2.48 gms. of boric acid (0.04 M.) and 2.36 gms. of procaine base (0.01 M.) are triturated with acetone and taken down to dryness on the water bath. A hard mass is obtained, white and solid, which softens to a doughy mass on the application of a moderate heat, as when placing the container over a low flame hot plate or immersing the container in boiling water. The material dissolves in water, giving a pH of about 7.1-7.3 bromthymol blue.

The formation and thesolution of the procaine.

dextrosoborate may also be obtained by mixing the ingredients in about 75 cc. of water and warming the solution at about 170 F. and below the'boiling point of the solution. Combination takes place easily.

Example 19.Using 1.65 gms. of benzocaine in the foregoing example, instead of procaine, and triturating with acetone and taking down to dryness, a grayish amber powder is obtained, pulverizable and dissolving in 100 cc. of glycerine.

Example 20.Substituting 1.72 ms. of sulfanilamide for the procaine in Example 18, and triturating in acetone and drying over the hot water bath, a slightly pinkish gray powder is formed, pulverizable and dissolving easily in water where it has an acid reaction.

Instead of dextrose, in the foregoing examples, laeyulose may be used.

Example 21. l0.32 grams of metol sulphate (HO.C6H4-NH.CH3)2.H2SO4-pmthy1 amino phenol sulphate (mol. wt. 344) representing 0.03 molar equivalents of the salt, equal to 0.06 molar equivalents of the metol base, may be ground into a paste with 3.18 gms. of NaaCOs (0.03 M.) and placed on the water bath and stirred to drive off the CO2 gas; for several minutes. A small amount of sodium sulphite may be present. Separately, 7.44 gms. ofboric'acid (0.12 M.) and 43.68 gms. (0.24 M.) of mannitol are dissolved and boiled in 150 cc. of water. There are, therefore, 2 molar proportions of boric acid to one molar proportion of metol base and two molar equivalents of the mannitol to one of the boric acid.

Separately are dissolved 44 gms. of sodium bisulphite in 100cc. of water and 115 gms. of potassium carbonate stirred in. A portion of the potassium carbonate is neutralized by the acid bibonate and this is then added to the carbonate- 1 base.

radicle of the metol sulphate.

gm. of H3303 are dissolved sulphite with the formation of the double salt of sodium potassium sulphite, NaKSOs, and the balance of the potassium carbonate is left to impart the desired alkalinity to the solution. 5 gms. of potassium bromide are dissolved in this solution. I

The mannitoboric acid solution is added to the metol solution neutralized with the sodium carsulphite solution. The final volume is made up to 500 cc. and it constitutes a developing bath for about half gallon of final volume. The addition of 20 gms. of hydroquinone and stirring brings out the metol hydroquinone compound and the stock solution, when properly diluted, with three volumes of Water, dissolves and. mixes easily.

Instead of the sodium carbonate, sodium acid carbonate may be used to neutralize the acid 5.04 gms. of NaI-ICOs, or 3.40 gms. of NaOH may be used to the above amount of metol sulphate.

Instead of mannitol, dextrose may be used to form the carbohydrate-boric acid complex in the above example. 43.20 gms. of dextrose may be used.

Example 22.-Cafiein alkaloid, C8H1002N4.H20, in. wt, 212.13. This alkaloid may be combined with a carbohydrate boric acid complex as follows: 2.912 gm. of mannitol (0.16 M.) and 2.48 and boiled up in about 75 cc. of water. The addition of 2.12 gm. of cafiiein alkaloid to the solution causes it to dissolve at once with the formation of caffein mannitoborate. The solution is acid to M. R. This is an illustration of how lessthan one molar equivalent of the carbohydrate was used to activate the boric acid present, and the solution of the cafiein borate took place. Caffein is a weak Example 23.Nupercaine base,

C2oH29O2N3.HC1

butyloxycinchoninic acid diethyl ethylene-- 1'3 diamide; m. wt. 379.72 may also form a salt of a carbohydrate boric acid complex 0.3432 gm. of

. the base (0.001 M.) may be stirred into a hot solution of 2.184 gm. of sorbitol (0.012 M.) and i m. wt. 300.68. 0.60136 gm. of pontocaine I-ICl is dissolvedin cc. of water; 0.106 gm. of NazCOs (0.001 M.) is used to precipitate the'nupercaine base, which is then redissolved in a previously prepared solution of 0.372 gm. of boric acid (0.006 M.) and 2.184 gm. of sorbitol (0.012 M.). Solution with the formation of pontocaine sorbitol borate takes place at once; is made up to 100 cc. with water and it then registers a pH of about 5.5-5.6 M. R. Color Chart. Example 25.-The formation of butyn salt of a carbohydrate boric acid complex may be illustrated as follows: butyn,

m. wt. 710.58. 0.7105 gm. of. butyn sulphate plex, the following may be done: eucupin alkaloid, isoamyl hydrocupreine, C24H3402N2, m. wt. 382.28.

1.9111 gm. of eucupin base (.005 M.) may be stirred into a previously prepared solution of 1.36 gm. of HsBOs (0.03 M.) and 7.23 gm. of sorbitol (0.04 M), in which the eucupin base soon dissolves. The solution made up to 100 cc. with water indicates an acid reaction to M. R. indicator.

Example 27.-To illustrate the formation of a soluble cellulose carbohydrate boric acid complex, the following may be done. 3.72 gm of boric acid (0.06 M.) may be dissolved in about cc. of boiling water and added on to 100 cc. of a 10% solution of hydroxyethyl cellulose. The pH of the solution is promptly lowered and is definitely acid to M. R. 3.34 gm. of sulfanilamide (0.02 M.) may then be stirred and the solution warmed on the hot plate until the sulfanilamide dissolves. The solution may be poured out on a glass plate and allowed to dry until a film is formed. 1

An excess of a carbohydrate alcohol in the presence of less boric acid may render the solue tion of a strong base linked to such an acid complex more strongly acid than a similar solution containing more boric acid and less of the carbohydrate alcohol. For instance, a 2.36% solution of procaine base in a 3.64% solution of mannitol (0.02 M.) to a 1.86% solution of boric acid (0.03'M.) registers a pH of about 6.2-6.5 Brom Thymol Blue (Color Chart) When in a similar solution the mannitol content is doubled,

to 7.28 gm. (0.04 M.), to 100 cc. of solution, the

The solution 14 pHis lowered to about 5.2-5.4; M. R. the amount of boric acid being lowered to 1.24 gm. in the 100 cc. solution (0.02 M.)

1 Less boric acid and more carbohydrate lowered the pH of the solution.

The various solutions illustrated in the above examples, as well as similar ones as of the present invention, either when used by themselves,

or with various vasoconstrictors, may be used with antioxidants to prevent oxidation.

These antioxidants may bethe usual bisulphites, sodium, or potassium bisulphite, sodium hydrosulphite, sodium metabisulphite. Acetone, sodium bisulphite, the aromatic aldehyde sodium bisulphite compounds, such as benzaldehyde sodium bisulphite and the like may be used.

sodium thiosulphate antioxidant may be used under certain conditions with the above amino,

aromatic salts of carbohydrate boric acid complexes alone, or it may be used in combination with the above. bisulphites and their addition products, or with various mixtures of the same. In connection with the sulfonamides, thiourea, allylthiourea and the like substances may be used as antioxidants.

The materials may be used either in solution form, or in powder; the carbohydrate-boric acid complexes may be previously prepared and added on to the base. to form the salt of the amino-aromatic compound with the complex upon dissolving in a suitable vehicle. Mixtures of the carbohydrate activators, boric acid, and the organic base may also be mixed in powder form, or stamped out into tablets, ready for final formulation when dissolved in a suitable veh cle as a solvent.

Example 28.-As an illustration of forming a salt of an amino-aromatic compound with a carbohydrate boric acid complex by the process of double decomposition, the following may be given: 4.72 gm. of procaine base (0.02 M.) may be combined in hot water with 1.84 gm. (0.04 M.) of oxalic acid to form monoprocaine oxalate.

Separately 29.12 gms. of mannitol (0.16 M.) may be dissolved in cc. of boiling water with 4.96 gm. of H3BO3 (0.08 M.) and 1.482 gm. of Ca(OI-I)2 (0.02 M.) may be stirred into the mannitol borate solution when the calcium hydroxide soon dissolves with the formation of calcium mannito-borate. This solution is now added to the solution of the procaine oxalate, when calcium oxalate precipitates at once. The filtrate contains the formed by double decomposition.

procaine mannito-borate which may beisolated by removing the solvent. 1

Example 29.--0.065 gm. of epinephrine base powder may be dissolved in 0.1514 gm. ofmannitoboric acid solution in 25 cc. of water. This is a one molar equivalent of the epinephrinebase to two molar equivalents of the mannito-monoboric acid. The solution registers a pH of about 6.5-6.7 brom thymal blue.

This completes the description of the products and processes of the present invention. It is to be understood that specific examples presented are intended to serve as illustrations of the general principles disclosed and are not intended to limit the invention in any way, asmany variations and modifications may be made within the spirit and scope of the invention and without the use of the inventive faculties.

This application is a continuation in part of my copending application Serial No. 417,712, filed November 3,. 1941, for Ahaesthctc: solutions,

which has issued as Patent,#2,382,54.6.

It is to be understood-that the boric; acid which is activated by thev polyhydroxy compounds named in the specification need not be exclusively-orthoboric acid, but may also be'in the form of metaboric acid, boric acid anhydride, .borax and; other boric acid compounds.

What I claim is: I p

l. A salt formed of an amino-aromatic base from the group consistin of alkyl and alkamine esters of an amino-aromatic acid with' boric acid, in the presence of an aliphatic polyhydroxy compound selected from the group consisting of erythritol, arabinose; araoitol, glucose, mannose,

gulose, galactose, fructose; sorbitol, mannitol, dulcitol, glucoheptose, fructo-heptose, iso-ma-nnidc, sorbide, m-annide, mannitan, sorbitan and pentaerythritol.

' .6,-.':Th e process of forming-a salt of claim 1;, which comprises the, steps of; dissolving the amino-aromatic base in a volatile vehiclftrituratingthe solution witha mixture of boric acid and the aliphatic polyhydroxy compound and drivingofi the volatile vehicle at a tenipera'turte below the boiling point of water. l

'7. The process of forming a salt of claim A which comprises the steps of dissolvin the amino-aromatic compound in a volatile solvent in which the formed sale is of limited solubility and combining the solution of said. amino-arc; matic compound in said volatile vehicle with a mixture of boric acid and the aliphatic polyhydroxy compound, stirring and heating the mix ture and then. removing the volatile solvent;

8. The process of forming a salt of claim '1, which. comprises the steps of bringing together a salt of the an1ino-arornatic compound and a salt of boric acid combined Witnthealiphatic polyhydroxy compound, in a solvent, resulting in ionic transposition. I

9. The process of forming a salt of claim 1, which comprises the steps of dissolving an oxalic acid salt of the amino-aromatic compoundsa-nd adding to the solution of said salta calcium salt of boric acid combined with the aliphatic polyhydroxy compound, filtering the precipitated calcium oxalate and removing the formed salt from the filtrate.

' DAVID CURTIS; No references cited. 

